Project Summary X-linked hypophosphatemia (XLH) is the most common form of heritable Rickets. Patients with XLH present with two related clinical pathologies; defective bone matrix mineralization and hypophosphatemia. The mineralization defect is primarily caused by the accumulation of mineralization inhibitors within the bone matrix, while hypophosphatemia is attributed to increased circulating levels of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23). Although the mutation that causes XLH has been identified as the phosphate-regulating endopeptidase homologue, X-linked (PHEX) gene, the factors that ultimately lead to poor mineralization and elevated FGF23 are not well described. My preliminary data implicates the protein sclerostin in both skeletal mineralization and phosphate metabolism regulation. The current proposal will test the hypothesis that sclerostin is a key regulator of skeletal mineralization and phosphate metabolism using both mechanistic and translational research aims. Aim 1 will investigate potential mechanisms of action using both in vitro and in vivo models while Aim 2 will test the use of Scl-Ab as a treatment option for XLH using the Hyp mouse model of XLH. My long-term goal is to become a leading independent researcher in the field of skeletal mineralization and mineral metabolism. In order to achieve these goals, I have chosen successful researchers to serve as mentors, including Dr. Anne George (primary mentor), an expert in skeletal mineralization, and Dr. Di Chen (co-mentor), an expert in skeletal development and Wnt signaling. The research described will serve as an ideal training vehicle for me to develop expertise in the use of cell culture and transgenic animal models, while also furthering my understanding of the systemic control of mineral metabolism. The training plan will focus on cell and molecular biology, endocrinology and the systemic control of mineral metabolism, and advanced training in grantsmanship, which will give me the tools necessary to build a successful independent research laboratory.